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Abstract

Background Patients with ischemia during stress testing and ambulatory ECG monitoring have an increased risk of cardiac events, but it is not known whether their prognosis is improved by more aggressive treatment with anti-ischemic drugs or revascularization.

Methods and Results The Asymptomatic Cardiac Ischemia Pilot study randomized 558 such patients who had coronary anatomy suitable for revascularization to three treatment strategies: angina-guided drug therapy (n=183), angina plus ischemia–guided drug therapy (n=183), or revascularization by angioplasty or bypass surgery (n=192). Two years after randomization, the total mortality was 6.6% in the angina-guided strategy, 4.4% in the ischemia-guided strategy, and 1.1% in the revascularization strategy (P<.02). The rate of death or myocardial infarction was 12.1% in the angina-guided strategy, 8.8% in the ischemia-guided strategy, and 4.7% in the revascularization strategy (P<.04). The rate of death, myocardial infarction, or recurrent cardiac hospitalization was 41.8% in the angina-guided strategy, 38.5% in the ischemia-guided strategy, and 23.1% in the revascularization strategy (P<.001). Pairwise testing revealed significant differences between the revascularization and angina-guided strategies for each comparison.

Conclusions A strategy of initial revascularization appears to improve the prognosis of this population compared with angina-guided medical therapy. A larger long-term study is needed to confirm this benefit and to adequately test the potential of more aggressive drug therapy.

In patients with coronary disease, ischemia during stress testing and AECG monitoring predicts a worsened prognosis.12 It is not known whether this is improved by aggressive treatment aimed at reducing ischemia. The NHLBI-sponsored ACIP Study (for list of participants, see Reference 33 ) was conducted to see whether a larger trial addressing this question was feasible. ACIP compared the relative efficacies of three treatment strategies in suppressing ischemia: (1) angina-guided drug therapy, (2) angina plus AECG ischemia–guided drug therapy, and (3) revascularization by either PTCA or CABG.

We previously reported that the revascularization strategy was more effective than either the angina-guided or ischemia-guided drug strategy in suppressing ischemia at 12 weeks and 1 year after randomization and was associated with a reduced 1-year mortality and morbidity.34 This report describes the 2-year clinical outcomes associated with these three treatment strategies.

Methods

The ACIP methodology and trial design have been published previously.5 The target population was clinically stable patients with angiographically documented coronary disease (≥50% stenosis in ≥1 major vessel or branch) suitable for revascularization. To be eligible, patients also had to have ischemia during exercise or pharmacological stress testing and at least one episode of asymptomatic ischemia during 48-hour AECG monitoring. Patients either were free of angina or had symptoms that could be well controlled by medical therapy. Patients with recent MI or unstable angina or who were unable to tolerate at least one of the two prespecified medical treatments were excluded. The ACIP protocol and consent forms were approved by the responsible institutional review boards. All patients provided informed consent before enrollment. An independent data and safety monitoring board reviewed clinical outcomes and the conduct and safety of the trial at 6-month intervals.

Patients were randomized to one of three initial treatment strategies: angina-guided medical treatment, ischemia-guided medical treatment, or revascularization. The angina-guided strategy consisted of anti-ischemic drug treatment sufficient to control angina. The ischemia-guided strategy added additional active drug therapy if ischemia was still present during AECG recording. Patients in the angina-guided strategy received placebo to maintain blinding. The revascularization strategy consisted of initial treatment with PTCA or CABG aimed at achieving the most complete revascularization possible by the method deemed most appropriate by the physician at the clinical site. After randomization, open-label active medication or nonprotocol revascularization was permitted as necessary to control angina.

Protocol anti-ischemic drug therapy consisted of titrated regimens of atenolol with addition of controlled-release nifedipine if needed or of sustained-release diltiazem with addition of sustained-release isosorbide dinitrate if needed. During the first 4 weeks after randomization, open-label medications were titrated upward to control angina if it was present. During the subsequent 8 weeks, placebo (angina-guided strategy) or active drug (ischemia-guided strategy) was added if ischemia was still present on repeat 48-hour AECG recordings. All patients received aspirin unless contraindicated. Patients were maintained on assigned treatment for a period of 1 year, at which time they were withdrawn from study medication and treated as deemed necessary by their physician.

Clinical Characteristics and Outcome Assessment

Prespecified clinical outcomes included death, MI, recurrent hospitalization for cardiac disease, and nonprotocol revascularization. An independent committee unaware of treatment assignment classified outcomes occurring within 1 year of enrollment using prespecified definitions. Outcomes occurring during the second year were reported as determined by the clinical sites and were not reviewed centrally.

Statistical Analysis

Data are reported for 558 patients randomized in 10 clinical centers6 for whom follow-up was 100% complete at 1 year and 97% complete at 2 years. On the final data edit, it was noted that 7 randomized patients should have been excluded for the following reasons: MI within 4 weeks (n=2, angina-guided strategy), PTCA within the previous 6 months (n=5: 2 in the angina-guided strategy, 2 in the ischemia-guided strategy, and 1 in the revascularization strategy). In addition, 22 patients in the revascularization strategy did not have PTCA or CABG within the specified time window. Analyses included these patients in their assigned groups according to the intention-to-treat principle.

Adverse outcomes were classified according to the following hierarchical scheme: (1) death; (2) death or MI; and (3) death, MI, or hospitalization for a cardiac condition. The latter included nonprotocol revascularization and any cardiac complication associated with a noncardiovascular admission. Outcome rates were calculated by Kaplan-Meier life table methods and compared by the log-rank test. Because of the risk of type 1 error with multiple post hoc comparisons, it was specified during the planning of ACIP that a value of α=.01 would be taken as showing some evidence for a significant difference and a value of α=.001 would be taken as showing strong evidence for a significant difference.

Results

Baseline Characteristics

Table 1⇓ summarizes the baseline characteristics of the 558 randomized patients, and Table 2⇓ summarizes baseline exercise testing and AECG monitoring data. Complete reports of baseline data have been published previously.3 Groups were well matched with regard to important baseline variables. Overall, 89% of randomized patients were receiving aspirin: 89% in the angina-guided strategy, 90% in the ischemia-guided strategy, and 88% in the revascularization strategy. During baseline treadmill exercise testing, there was a nonsignificant tendency toward more strongly positive ischemic responses in the revascularization strategy. In each group, 33% of patients had angina during baseline treadmill exercise testing; the remainder had asymptomatic ischemia. During baseline AECG monitoring, there was a tendency for the revascularization group to have more episodes and a greater total ischemic time. Only 61 of 558 patients (11%) had symptomatic as well as asymptomatic episodes.

Protocol Drug Treatment

Compared with the angina-guided strategy, patients randomized to the ischemia-guided strategy received significantly more active anti-ischemic medication, and those randomized to the revascularization strategy received significantly less.3 At 1 year, among patients assigned to receive atenolol plus nifedipine, the mean daily dose of active medication for the angina-guided strategy was atenolol 64 mg and nifedipine 42 mg; for the ischemia-guided strategy, atenolol 128 mg and nifedipine 58 mg; and for the revascularization strategy, atenolol 65 mg and nifedipine 46 mg. Among those assigned to receive diltiazem plus isosorbide dinitrate, the mean daily dose of active medication for the angina-guided strategy was diltiazem 170 mg and isosorbide dinitrate 69 mg; for the ischemia-guided strategy, diltiazem 276 mg and isosorbide dinitrate 86 mg; and for the revascularization strategy, diltiazem 159 mg and isosorbide dinitrate 58 mg.

Protocol Revascularization

Within the revascularization strategy, PTCA was selected for 102 patients and CABG for 90 patients. Eight patients selected for PTCA subsequently refused the procedure, and 2 had the procedure outside of the specified time window (which was 6 weeks for staged PTCA, 4 weeks otherwise). This left 92 patients who underwent protocol PTCA within the specified time window. Eleven patients selected for CABG subsequently refused the procedure, and 1 had the procedure outside of the 4-week time window. This left 78 patients who underwent protocol CABG within the specified time window. All randomized patients were included in their assigned treatment groups for statistical analysis according to the intention-to-treat principle.

Clinical Outcomes

Figs 1 through 3⇓⇓⇓ show 2-year event rates for the three treatment strategies. Mortality for the angina-guided strategy was 6.6%, for the ischemia-guided strategy 4.4%, and for the revascularization strategy 1.1% (Fig 1⇓). Pairwise testing showed the difference between the angina-guided and revascularization strategies to be significant at the P<.005 level. The differences between the ischemia-guided and revascularization strategies (P=.05) and between the angina-guided and ischemia-guided strategies (P=.34) were not significant by ACIP predefined criteria.

Two-year cumulative mortality rates for three treatment strategies. Significant differences were seen between revascularization and angina-guided strategies (P<.005) and between revascularization and ischemia-guided strategies (P<.05). Angina-guided and ischemia-guided strategies were not significantly different from each other (P=.34).

Two-year cumulative rates of death or MI. Revascularization strategy was significantly different from angina-guided strategy (P<.01). Differences were not significant between revascularization and ischemia-guided strategies (P=.12) and between angina-guided and ischemia-guided strategies (P=.30).

Two-year cumulative rates of death, MI, or cardiac hospitalization. Differences were significant between revascularization strategy and both angina-guided and ischemia-guided strategies (P<.003). The latter were not significantly different from each other (P=.48).

Rates for the end point of death or myocardial infarction were 12.1% for the angina-guided strategy, 8.8% for the ischemia-guided strategy, and 4.7% for the revascularization strategy (Fig 2⇑). Pairwise testing revealed the difference between the angina-guided and revascularization strategy to be significant at the P<.01 level. Differences were not significant between the angina-guided and ischemia-guided strategies (P=.30) or between the ischemia-guided and revascularization strategies (P=.12).

Rates for the end point of death, myocardial infarction, or recurrent hospitalization (including nonprotocol revascularization) were 41.8% for the angina-guided strategy, 38.5% for the ischemia-guided strategy, and 23.1% for the revascularization strategy (Fig 3⇑). Pairwise testing revealed the differences between the revascularization strategy and both the angina-guided and ischemia-guided strategies to be significant at the P<.005 level. The angina-guided and ischemia-guided strategies were not significantly different from each other (P=.48).

Table 3⇓ shows the 2-year event frequencies for each strategy and the calculated reduction in event rates for the ischemia-guided and revascularization strategies relative to the angina-guided strategy.

As noted above, 170 of the 192 patients assigned to the revascularization strategy underwent the assigned procedure within the prespecified time window. Of the 92 undergoing PTCA, 2-year event rates were 1.1% (1 patient) for mortality; 5.5% (5 patients) for death or MI; and 31.7% (29 patients) for death, MI, or recurrent hospitalization. The corresponding rates for the 78 patients undergoing CABG were 0% for mortality; 2.7% (2 patients) for death or MI; and 12.9% (10 patients) for death, MI, or hospitalization. When patients undergoing PTCA and CABG were compared, differences were statistically significant only for the latter end point (death, MI, or hospitalization; P=.005). Among the medical treatment groups, there were no significant differences in any of these end points between patients assigned to diltiazem/isosorbide dinitrate and those assigned to atenolol/nifedipine.

Nonprotocol Revascularization

As shown in Table 4⇓, the 2-year rates of nonprotocol revascularization were 29% for both medical treatment strategies and 11% for the revascularization strategy. Most of this difference was because of a lower rate of recurrent CABG in the revascularization strategy.

Risk Reduction in Angiographic Subgroups

Table 5⇓ shows the 2-year frequency of adverse clinical outcomes in different angiographic subgroups. Patients with at least 50% stenosis in the proximal LAD who were randomized to a medical treatment strategy had higher event rates than did patients without a significant proximal LAD stenosis. This was not the case for patients randomized to the revascularization strategy. The data suggest a tendency for the benefit of revascularization to be concentrated in those with proximal LAD stenoses (P=.013 for difference between relative risks). There was a similar tendency in patients with three-vessel disease compared with those with one- or two-vessel disease (P=.015 for difference between relative risks).

Two-Year Event Frequencies and Relative Risk Reduction by Revascularization in Different Angiographic Subgroups

Discussion

These results indicate that initial revascularization may substantially improve the 2-year prognosis of patients with objective evidence of ischemia and suitable coronary anatomy, even if their angina is well controlled on conservative medical therapy. There have been three major previous trials of revascularization and prognosis: CASS, the VA Study, and the European Study. Both CASS and the VA Study reported an overall negative effect of CABG on survival,78 whereas the European Study showed an overall benefit.9 A recent meta-analysis also found an overall survival benefit of CABG.10 This meta-analysis and individual subgroup analyses of the three major trials11121314 suggested that improvement in prognosis is concentrated in specific high-risk subgroups. Consequently, it is currently accepted that bypass surgery improves survival in patients with left main coronary artery disease and in those with left ventricular dysfunction who have two- or three-vessel disease involving the proximal LAD.15 Such patients were not included in ACIP. No patient had left main disease >50%, and only 5% had the combination of LAD stenosis and ejection fraction <50%. The results therefore indicate that revascularization may be indicated to improve prognosis in a broader group of patients.

Previous studies of CABG and prognosis were begun in the 1970s and early 1980s, and their results reflect the surgical and medical approaches in use at that time. Their results may underestimate the benefits of revascularization by current techniques, which now include internal thoracic artery grafts and other arterial conduits, improved methods of myocardial preservation, and the routine postoperative use of aspirin. PTCA, which currently accounts for approximately half of revascularization procedures, was not yet available when these previous trials were initiated. By contrast, ACIP revascularization was done between November 1991 and January 1993 using currently accepted techniques, with the goal of achieving as complete revascularization as possible. Until a larger study is completed, ACIP provides the best available data regarding revascularization for prognosis and the only randomized data comparing reasonably current techniques with medical therapy.

Implications of ACIP Design

This study compares the clinical outcomes for three initial therapeutic strategies according to the intention-to-treat principle. For patients who could not be adequately controlled despite maximal medical therapy, revascularization could be considered. Consequently, 29% of patients randomized to medical treatment strategies underwent nonprotocol revascularization during the 2 years of follow-up. Because “crossovers” would tend to diminish differences between medical and revascularization strategies, the design of ACIP is unlikely to have exaggerated the benefits of revascularization. Examining the outcomes associated with different therapeutic options exercised at a given point in time is also the most clinically relevant comparison.

Limitations

ACIP was a pilot study. As such, it was not planned to have sufficient statistical power to detect differences in clinical outcomes. The difference between the angina-guided and revascularization strategies in 2-year mortality is based on only 14 deaths (12 in the angina-guided strategy and 2 in the revascularization strategy). The results for death or nonfatal MI are based on only 31 events (22 in the angina-guided strategy and 9 in the revascularization strategy). Although the dramatic differences seen produced a statistically significant result, there are too few events to allow for an accurate measurement of effect size. Therefore, although we observed a sixfold difference in mortality in favor of revascularization over conservative medical therapy, the confidence bounds around this estimate are wide.

Previous studies of revascularization showed that the patients most likely to benefit from revascularization are those who have the greatest risk of cardiac events with medical therapy.10 ACIP used the combination of stress testing and AECG monitoring to identify high-risk patients. However, this may not be the best way to select patients who will benefit from revascularization. Although several previous studies have shown that AECG monitoring identifies high-risk patients,12 other studies show that this may not be true in all populations.16 This raises the possibility that the requirement of ischemia during AECG monitoring in addition to ischemia during stress testing may be unnecessarily restrictive. It is also possible that another test or combination of tests might be more effective in selecting the appropriate high-risk subgroup. An ACIP substudy looked at the relation between AECG ischemia, stress single photon emission computed tomography perfusion imaging, and coronary anatomy.17 It found that the only predictor of AECG ischemia was the presence of ST depression during exercise testing, whereas the most important predictor of perfusion abnormalities was the severity of coronary stenoses on angiography. The present study found that those patients with proximal LAD stenoses and those with three-vessel disease tended to have higher event rates and to derive greater benefits from revascularization. It is therefore possible that nuclear perfusion imaging will prove useful in better characterizing which high-risk patients will benefit most from revascularization. The role of various tests in doing so remains an extremely important unresolved question that needs to be studied as part of a larger, adequately powered trial.

The small sample size of ACIP limited its ability to address the issue of whether more aggressive medical therapy improves prognosis. Clinical outcome rates for the ischemia-guided drug treatment strategy were intermediate between angina-guided drug therapy and revascularization. When the ischemia-guided strategy is compared with the angina-guided strategy, the observed reduction in mortality is 33% (4.4% versus 6.6%) and in death plus MI, 27% (8.8% versus 12.1%). Although these results were not statistically significant, these trends may be important, especially because the ACIP drug titration scheme did not maximize dosage in the ischemia-guided strategy.4 Because other studies have also provided supporting evidence for an influence of more aggressive anti-ischemic therapy on prognosis,1819 this issue needs to be resolved by further research.

Another limitation of this study relates to the fact that ACIP enrolled patients between 1991 and 1993, before the results of several other important secondary prevention trials were available. These studies have shown that aggressive cholesterol lowering reduces AECG ischemia20 and improves the prognosis of patients with known coronary disease.2122 It is therefore possible that aggressive cholesterol lowering might reduce the apparent benefit of revascularization. However, both the Scandinavian Simvastatin Survival Study21 and the Cholesterol and Recurrent Events Study22 found that prognostic improvements with aggressive lipid-lowering therapy were apparent only after ≈2 years of therapy. The present study indicates that revascularization has a more immediate benefit, and the recently published NHLBI Post-CABG study23 shows that lipid-lowering therapy also retards the development of atherosclerosis in bypass grafts. Taken together, these results suggest that future research will show that the clinical benefits of lipid-lowering therapy and revascularization are complementary.

Conclusions

Until a larger prognosis trial is done, ACIP provides the most current data comparing a strategy of immediate revascularization with conservative medical therapy. The 2-year outcome data reported here are sobering in that, if confirmed in a larger trial, they would significantly expand the population for which revascularization is indicated to improve prognosis. A larger study is therefore needed to confirm this benefit using current revascularization techniques in a setting of more aggressive lipid-lowering therapy and to adequately test the prognostic potential of more aggressive anti-ischemic drug therapy.

Selected Abbreviations and Acronyms

ACIP

=

Asymptomatic Cardiac Ischemia Pilot Study

AECG

=

ambulatory ECG

CABG

=

coronary artery bypass graft surgery

LAD

=

left anterior descending coronary artery

MI

=

myocardial infarction

PTCA

=

percutaneous transluminal coronary angioplasty

Acknowledgments

This study was funded by the National Heart, Lung, and Blood Institute, Division of Heart and Vascular Disease, National Institutes of Health, Bethesda, Md, by research contracts HV-90-07, HV-90-08, and HV-91-05 to HV-91-14. Study medications and placebo were donated by Zeneca Pharmaceuticals Group, Wilmington, Del; Marion-Merrell Dow, Kansas City, Mo; and Pfizer, New York, NY. Support for ECG data collection was provided in part by Applied Cardiac Systems, Laguna Hills, Calif; Marquette Electronics, Milwaukee, Wis; Mortara Instrument, Milwaukee, Wis; and Quinton Instruments, Seattle, Wash. Some centers had partial support from General Clinical Research Center grants. A complete list of the ACIP investigators and centers participating in the ACIP study was published previously.3